The present invention relates to lotions stably containing maxacalcitol, which are useful as external medicines. More specifically, the present invention relates to lotions useful as external medicines wherein chemical stability and percutaneous absorption of maxacalcitol as an active ingredient can be controlled by regulating the composition of components.
Some classes of active vitamin D3 derivatives such as 1xcex1,3xcex2-dihydroxy-20xcex1-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10(19)-pregnatriene (22-oxa-1xcex1,25-dihydroxyvitamin D3; herein also referred to as maxacalcitol) have skin epidermal cell growth-inhibiting and differentiation-inducing effects and are expected to have pharmacological effects against psoriasis (JPA Nos. 267550/86 and 183534/88).
Maxacalcitol is known to be chemically unstable and rapidly decompose especially in aqueous solutions. Generally, the following techniques have been proposed to improve stabilization of vitamin D-related derivatives.
(1) stabilization by adding various amino acids (alanine, valine, lysine, etc.: JPA No. 17/87);
(2) stabilization by combination of ascorbic acid or a salt thereof with a chelating agent (JPA No. 44845/86);
(3) stabilization by adding ascorbic acid alone (JPA No. 238936/93); and
(4) stabilization by inclusion in cyclodextrin (JPA Nos. 83021/88 and 128417/76).
However, these techniques have disadvantages such as they involve a complex procedure or have an insufficient stabilization effect, and do not suffice to prepare a lotion stably maintaining maxacalcitol.
As to percutaneous absorption in the category of biological properties, the use of absorption promoters is recommended and the addition of unsaturated fatty acids such as oleic acid or the use of chemicals such as AZONEs has been reported (Morimoto et al. in the program and abstracts of lectures, p. 21, Proceedings of the eighth transdermal therapeutic system symposium, Tokyo, Feb. 21, 1996).
However, these absorption enhancers are not preferable for use in preparations that are often administered (applied) repeatedly, because their enhancing mechanisms depend on providing high absorption efficiency by damaging the skin.
Thus, the need to develop lotions stably maintaining maxacalcitol and having excellent percutaneous absorption continue to exist.
As for the behavior of its stability in aqueous solutions, maxacalcitol is known to remain stable if the pH of the solutions is shifted to an alkaline side. However, alkaline preparations are highly irritant to skin and side effects possibly increase. Therefore, when maxacalcitol is formulated in preparations for external medication, it is desirable to attain stabilization of maxacalcitol in a solution at or around neutral pH.
An object of the present invention is to provide a lotion wherein maxacalcitol as an active ingredient is stably maintained, especially a lotion having a pH at or around neutrality.
Another object of the present invention is to simply solve the problem of chemical stabilization of maxacalcitol, which could not be readily attained in the prior art, by a convenient method of adding a specific type of nonionic surfactant and a polyhydric alcohol.
Still another object of the present invention is to provide a lotion having particularly excellent percutaneous absorption by regulating the compounded amount of a less skin-irritating polyhydric alcohol to control the percutaneous absorption.
As a result of careful studies conducted to solve the above problems, we unexpectedly found that a lotion containing maxacalcitol as an active ingredient stably maintains the active ingredient even at or around neutral pH upon addition of a specific nonionic surfactant. The present invention successfully achieved not only solubilization of oil-soluble materials but also a high stabilization effect by using a specific type of nonionic surfactants among which have heretofore been used as solubilizers for materials that are slightly soluble in water. This was a quite unexpected discovery because no report had been made of the ability of any nonionic surfactants to simultaneously achieve both solubilization and stabilization of oil-soluble materials (maxacalcitol in the specification). Moreover, we succeeded in controlling both of heat stability and percutaneous absorption of the active ingredient maxacalcitol by selecting a polyhydric alcohol, a nonionic surfactant and a solubilizer as additives in a lotion, and also succeeded in establishing an optimal composition for both heat stability and percutaneous absorption in a lotion prepared from specific components. The present invention was completed based on these findings.
Accordingly, the present invention provides a lotion comprising maxacalcitol as an active ingredient and a nonionic surfactant as an additive.
According to a preferred embodiment of the present invention, an ether-type surfactant is used as a nonionic surfactant.
According to a more preferred embodiment of the present invention, a block copolymer-type nonionic surfactant or a polyoxyethylene alkyl ether is used as an ether-type surfactant.
According to a still more preferred embodiment of the present invention, a Pluronic-type or polyoxyethylene cetyl ether-type surfactant is used as an ether-type surfactant.
Preferably, Pluronic(trademark) F-68 or Cetomacrogol(trademark) 1000 is used as a Pluronic-type or polyoxyethylene cetyl ether-type surfactant, respectively.
More preferably, a lotion of the present invention contains 0.1-20% by weight of Pluronic F-68 or 0.1-2% by weight of Cetomacrogol 1000 as a surfactant.
Most preferably, a lotion of the present invention contains 1-5% by weight of Pluronic F-68 or 0.5-2% by weight of Cetomacrogol 1000 as a surfactant.
According to one embodiment of the present invention, there is provided a lotion which, besides a nonionic surfactant, further comprises a polyhydric alcohol and a solubilizer as additives.
Preferably, a lotion of the present invention contains a glycol as a polyhydric alcohol, an ether-type surfactant as a nonionic surfactant and a monohydric alcohol as a solubilizer.
More preferably, a lotion of the present invention contains propylene glycol and/or 1,3-butylene glycol as a polyhydric alcohol, a polyoxyethylene alkyl ether or a Pluronic-type surfactant as a nonionic surfactant and ethanol or isopropanol as a solubilizer.
More preferably, a lotion of the present invention contains propylene glycol and 1,3-butylene glycol as polyhydric alcohols, Cetomacrogol 1000 as a nonionic surfactant and ethanol as a solubilizer.
An especially preferred lotion of the present invention contains 1-70% by weight of propylene glycol, 1-45% by weight of 1,3-butylene glycol, 0.1-5% by weight of Cetomacrogol 1000, 1-20% by weight of ethanol, and the balance being water.
An especially preferred lotion of the present invention contains 50-70% by weight of propylene glycol, 1-20% by weight of 1,3-butylene glycol, 0.1-2% by weight of Cetomacrogol 1000, 1-20% by weight of ethanol, and the balance being water.
Most preferably, a lotion of the present invention contains 50-70% by weight of propylene glycol, 1-20% by eight of 1,3-butylene glycol, 1% by weight of Cetomacrogol 1000, 1% by weight of ethanol, and the balance is water.
The present invention relates to lotions comprising maxacalcitol as an active ingredient and a nonionic surfactant as an additive, as well as lotions which, besides a nonionic surfactant, further contain a polyhydric alcohol and a solubilizer as additives.
1xcex1,3xcex2-Dihydroxy-20xcex1-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10(19)-pregnatriene (22-oxa-1xcex1,25-dihydroxyvitamin D3; herein also referred to as maxacalcitol) contained as an active ingredient in lotions of the present invention is a known vitamin D3 derivative and can be synthesized by the process described in JPA No. 267550/86, for example.
The amount of maxacalcitol contained in lotions of the present invention is a therapeutically effective amount for the skin disease to be treated, normally within the range of from about 1 xcexc/g to about 200 xcexcg/g, preferably about 2 xcexcg/g to about 100 xcexcg/g.
Nonionic surfactants used in the present invention have generally been used as solubilizers for slightly soluble materials. According to the present invention, however, nonionic surfactants are added not only to solubilize oil-soluble materials but also to improve heat stability of the active ingredient maxacalcitol. Therefore, the type of nonionic surfactants is not specifically limited in so far as they can simultaneously achieve solubilization and stabilization of the active ingredient maxacalcitol, but ether-type surfactants are preferred.
Among ether-type surfactants, Pluronic-type surfactants (polyoxyethylene/polyoxypropylene glycol) classified into block copolymer-type nonionic surfactants or polyoxyethylene alkyl ethers are especially preferred.
Specific examples of Pluronic-type surfactants include F-68 (trade name of polyoxyethylene (160)/polyoxypropylene (30) glycol available from Asahi Denka Kogyo K.K.) having hydrophilic physical properties. F-68 brings about advantageous effects typically at 0.1-20% by weight, preferably at 1-5% by weight.
Specific examples of polyoxyethylene alkyl ethers include Cetomacrogol 1000 belonging to cetyl ethers. Cetomacrogol 1000 brings about advantageous effects typically at 0.1-2% by weight, preferably at 0.5-2% by weight.
As described above, nonionic surfactants function to both stabilize and solubilize the active ingredient maxacalcitol in lotions of the present invention.
Moreover, by adding the above nonionic surfactants in lotion the pH of preparations can be adjusted to at or around neutrality without decreasing thermal stability of maxacalcitol. The above nonionic surfactants act to physically stabilize external medicines in general, and emulsion-type medicines in particular, so that they are well suitable for incorporation into lotions from both aspects of widely usage as pharmaceutical excipient and material cost.
However, the other class of nonionic surfactants, i.e. ester-type surfactants (polyoxyethylene fatty acid esters) showed contrastive results in maxacalcitol stabilization effect as compared to their satisfactorily solubilization effect. Thus, surfactants can be differentiated by differences of properties in terms of chemical structures.
According to one embodiment of the present invention, the lotion further comprises a polyhydric alcohol and a solubilizer as additives besides a nonionic surfactant.
Polyhydric alcohols suitable for lotions of the present invention have such physical properties that they are generally added as wetting (moisturizing) agents in conventional external preparations. In the present invention, they are added not only for this function but also to control or improve thermal stability of the active ingredient maxacalcitol.
The type of polyhydric alcohols is not specifically limited so far as they can control or improve thermal stability of the active ingredient maxacalcitol, but dihydric alcohols are preferred. Examples of dihydric alcohols include glycols such as propylene glycol, 1,3-butylene glycol, etc.
Solubilizers suitable for lotions of the present invention are reagents for solubilizing the active ingredient maxacalcitol. Solubilizers include, for example, monohydric alcohols such as ethanol or isopropanol. A preferred solubilizer is ethanol.
The ranges of the proportions of specific components in which both thermal stability and percutaneous absorption can be controlled in lotions of the present invention are as follows.
As to Cetomacrogol 1000 among polyoxyethylene cetyl ethers, both of the above properties can be controlled at a proportion of 0.1-5% by weight.
As to ethanol, both of the above properties can be controlled at a proportion of 1-20% by weight.
As to propylene glycol, both of the above properties can be controlled at a proportion of 0-70% by weight.
As to 1,3-butylene glycol, both of the above properties can be controlled at a proportion of 0-45% by weight.
Pharmaceutical properties and specific proportions of various additives are described below as a guide to a proposal of optimal pharmaceutical formulations.
As to Cetomacrogol 1000, 0.1-2% by weight is a suitable proportion considering both stability and percutaneous absorption.
As to ethanol, 1-20% by weight is a suitable proportion considering both stability and percutaneous absorption.
Propylene glycol mainly has effect on percutaneous absorption and may be added at a variable proportion up to 70% by weight based on actual application in external medicines. Proportions of 0-50% by weight are suitable for preparations that are required to have low absorption, while proportions of 50-70% by weight are suitable for preparations that are required to have high absorption. However, it should be noted that propylene glycol has a concentration-dependent negative effect on thermal stability of maxacalcitol in contrast with its percutaneous absorption.
1,3-Butylene glycol mainly has effect on thermal stability and may be added at any concentration up to 45% by weight based on actual application in external medicines. However, it should be noted that considering percutaneous absorption, 1,3-butylene glycol has no effect when high percutaneous absorption is required.
As described above, propylene glycol and 1,3-butylene glycol have conflicting pharmaceutical properties, so they can be added either alone or in combination in any proportions based on their contributory properties described above in accordance with the method and purpose of use.
For example, preparations having both high chemical stability and high percutaneous absorption as recommended herein contain, as base material, 50-70% by weight of propylene glycol, 0-20% by weight of 1,3-butylene glycol, 0.1-2% by weight, preferably 1% by weight, of Cetomacrogol 1000, and 1-20% by weight, preferably 1% by weight, of ethanol.
The above formulations are generally applicable in the field of external medicines from both aspects of application in products and product economy and their practical feasibility is very high.
If necessary, lotions of the present invention may further contain preservatives such as paraoxybenzoic acid esters and sorbic acids, or additives for improving commercial quality including thickeners such as CMC-Na, wetting (moisturizing) agents, organoleptic agents such as menthol, isopropanol, etc.
The process for preparing lotions of the present invention is not specifically limited. For example, a specific amount of maxacalcitol is dissolved in a specific amount of a solubilizer such as ethanol. In a separate step, a specific amount of a nonionic surfactant is dissolved in an appropriate buffer (such as phosphate buffer). Then, the above two solutions are mixed into a lotion. Alternatively, a mixture of the above two solutions may optionally be combined with a specific amount of a polyhydric alcohol and finally made up with the same buffer to give a lotion.
Lotions of the present invention can be used to treat various cases of psoriasis such as psoriasis vulgaris, psoriasis pustulosa, psoriasis guttata, erythroderma psoriaticum, psoriasis arthropathica, psoriasis gravis. The dose depends on the condition of the disease or other factors, but preferably a lotion containing 1 xcexcg/g to 200 xcexcg/g of maxacalcitol is administered once to several times per day.